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Home , Warfarin necrosis

CASE REPORT

Warfarin-Induced in Patients With Low Levels

Marino Marčić1, Ljiljana Marčić2, and Marina Titlić1

1 Department of Neurology, School of Medicine, University of Split, Split, Croatia 2 Department of Radiology, School of Medicine, University of Split, Split, Croatia

Received: 31 Oct. 2014; Accepted: 28 May 2015

Abstract- -induced skin necrosis (WISN) is a rare complication of therapy associated with a high incidence of morbidity and mortality requiring immediate drug cessation. At particular risk are those with various thrombophilic abnormalities, especially when warfarinisation is undertaken rapidly with large loading doses of warfarin. Cutaneous findings include petechiae that progress to ecchymosis and hemorrhagic bullae. With the increasing number of patients anticoagulated as out-patients for thromboprophylaxis, we are concerned that the incidence of skin necrosis may increase. We present a case of WISN with low protein C level. He was a 50-year-old male who came to our department because of acute infarction in irrigation area of the superior cerebellar artery. He had intermittent atrial fibrillation and was started on anticoagulant therapy. After few day of therapy, he developed skin necrosis, and his level of protein C was low. Warfarin-induced skin necrosis is a rare but serious complication that can be prevented by routine screening for protein C, protein S or antithrombin deficiencies or for the presence of antiphospholipid antibodies before beginning warfarin therapy. © 2016 Tehran University of Medical Sciences. All rights reserved. Acta Med Iran, 2016;54(8):551-554.

Keywords: Anticoagulant; Coumarins; Warfarin; ; Protein C;

Introduction necrotic (6). Dermal biopsy demonstrates ischemic necrosis of the cutaneous tissue with cutaneous vessel Stroke is one of the most significant risks associated thrombosis and surrounding interstitial hemorrhage with atrial fibrillation. Non-valvular atrial fibrillation (7,8). Protein C is a 62-kD, -dependent (AF) is the most common cause of cardioembolic stroke glycoprotein synthesized in the liver. It circulates in the and a powerful risk factor for strokes with overall risk blood as an inactive zymogen at a concentration of 4 ranges from 2.5% to 4% per year (1). Oral μg/mL (9). Its activation into the serine-protease-like (OAC) reduce this risk, but also increase enzyme, activated protein C (aPC), is catalyzed by the risk of hemorrhagic stroke and major bleeding. when it is bound to the endothelial Among all other side-effects of warfarin therapy, skin proteoglycan thrombomodulin (10,11). Activated necrosis is a rare but serious (2). Warfarin-induced skin protein C (aPC) exerts its anticoagulant activity necrosis (WISN) occurs in only 0.01%-0.1% of patients primarily through inactivation of factors Va taking the drug (3). WISN develops mainly in middle- and VIIIa, which are required for activation and aged women who are usually perimenopausal, obese and thrombin generation. The catalytic activity of activated have been treated for deep vein thrombosis or protein C (aPC) is greatly enhanced by the vitamin K- pulmonary embolism (4). The site of the lesion is dependent cofactor protein S (12). A deficiency of random and unpredictable, but the breast is the most activated protein C (aPC) disturbs the delicate balance common site in women, followed by the buttocks and between procoagulant and anticoagulant proteins and thighs. In men with WISN involvement of penile skin engenders a prothrombotic environment. The role of may is common (5). The skin lesions of WISN begin as activated protein C (aPC) and other anticoagulant erythematous macules and, if appropriate therapy is not proteins in this balance appear to be especially important initiated promptly, evolve to become purpuric and in the slow-flowing venous circulation, in which there is

Corresponding Author: M. Marcic Department of Neurology, School of Medicine, University of Split, Split, Croatia Tel: +385 21 556550, Fax: +385 21 556550, E-mail address: [email protected] Warfarin-induced skin necrosis prolonged exposure of procoagulant proteins and intravenous unfractionated , vitamin K, and fresh platelet phospholipids to the vessel wall. This may frozen plasma. Therapeutic heparinization, initially with explain, in part, why appears to be unfractionated, then with low molecular weight heparin associated primarily with venous thrombosis. There is a was continued for two weeks, during which time her calf lot of causes of acquired protein C deficiency: acute began to heal. Because of the strong risk for another thrombosis, warfarin therapy, liver disease, vitamin K stroke, we introduced in therapy novel anticoagulant deficiency, , disseminated intravascular therapy (dabigatran, in daily doses of 300 mg). His calf coagulation (DIC) and hematopoietic stem cell healed with no permanent skin damage. After 6 months, transplantation (13,14). With the increasing number of he did not have any new neurological complications. patients’ anticoagulated as out-patients for thromboprophylaxis, incidence of skin necrosis may Discussion increase. Warfarin-induced skin necrosis is rare, but serious Case Report side effect of anticoagulant therapy. This side effect typically appears during the early 10 days of therapy. At A 50-year-old male, came to our department with particular risk are those with various thrombophilic ataxia, speech problems, nausea, and vomitus. He had abnormalities, especially when warfarinisation is irregular heart rhythm because of intermittent atrial undertaken rapidly with large loading doses of warfarin. fibrillation. During the examination, he was eupneic, The pathogenesis of WISN is still obscure. Thrombosis, afebrile, with irregular heart rhythm. In the neurologic hypersensitivity, hemorrhage, factor VII deficiency, examination, we noticed truncal ataxia, left-hand protein C and S deficiency, and direct toxic effects of dysmetria, and he was dysarthric. The platelet count was warfarin have been suggested as potential mechanisms, 220×103/µL. CT scan showed acute ischemic lesion in but other hypercoagulable conditions such as lupus irrigation territory of the superior cerebellar artery which anticoagulant, factor V Leiden or antithrombin III was confirmed by MR two days after. During deficiency have also been associated with skin necrosis. hospitalization newly diabetes mellitus was discovered, Some cases occur in association with a familial and peroral therapy was started. 24 hour ECG recording, deficiency of protein C or protein S, and hereditary showed intermittent atrial fibrillation. The cause of his protein C deficiency is considered a major risk factor. stroke was intermittent atrial fibrillation, and his Heterozygous protein C deficiency is inherited in an CHADS-VASC score was 5. autosomal dominant fashion. In type I deficiency, there is a quantitative deficiency in the plasma protein C concentration, and type II protein C deficiency is associated with decreased functional activity and normal immunologic levels of protein C We represented a patient with an embolic stroke which is a candidate for anticoagulant therapy. Because of high risk for the new embolic incident; initially, we gave him a warfarin in a total dosage of 5 mg, inspite of low levels of protein C. He developed skin necrosis the second day of therapy, so we discontinued warfarin. When warfarin therapy is started, there is a more rapid fall in the concentration of protein C than of the other vitamin-K-dependent

Figure 1. Skin necrosis induced by warfarin procoagulant factors. The temporary hypercoagulable state which results is believed to lead to the development We introduced anticoagulant therapy with warfarin of WISN in susceptible individuals (16). The use of in a total dosage of 5 mg/D. He had low levels of protein large loading doses of warfarin may exacerbate this C (0.39, referent interval is 0.7-1.4). On the second day effect and particularly at risk are those with an inherited of anticoagulant therapy, his INR was 1.8, and he deficiency of protein C or other impairment of the developed an area of extremely tender erythema on her protein C pathway. Patients known to be at risk of left calf, surrounded by bruising. This was recognized as WISN (those with a previous episode, protein C or S early skin necrosis, and he was immediately treated with deficiency and, our data suggest, antiphospholipid

552 Acta Medica Iranica, Vol. 54, No. 8 (2016) M. Marcic, et al. antibodies) should also be warfarinised in this gradual protein C and S activity. Anadolu Kardiyol Derg way or treated with novel anticoagulant therapy, as what 2008;8:E22. have been done with our patients (17). A consequence of 5. ssex DW, Wynn SS, Jin DK. Late onset warfarin-induced the growth in the number of indications for warfarin skin necrosis: Case report and review of the literature. therapy is that many patients are now started on warfarin Am J Hematol 1998;57:233-7. and rapid warfarinisation in the out-patient setting 6. De Franzo AJ, Marasco P, Argenta LC. Warfarin-induced without concomitant heparinization may put some necrosis of the skin. Ann Plast Surg 1995;34:203-8. patients, such as those with undetected thrombophilic 7. Ad-El D, Meirovitz A, Weinberg A, Kogan L, Arieli D, abnormalities, at risk of WISN (18). The more gradual Neuman A, et al. Warfarin skin necrosis: Local and approach, using low-dose warfarin and aiming to systemic factors. Br J Plast Surg 2000;53:624-6. achieve a therapeutic INR in 10–12 days would lessen 8. Enzenauer RJ, Berenberg JL, Campbell J. Progressive this risk without compromising the treatment of patients warfarin anticoagulation in protein C deficiency: a who are being selectively anticoagulated. In patients therapeutic strategy. Am J Med 1990;88:697-8. with high risk for new embolic stroke and with known 9. Dahlbäck B. Protein S and C4b binding protein: risk of WISN (those with a previous episode, protein C components involved in the regulation of the protein C or S deficiency and, our data suggest, antiphospholipid anticoagulant system. Thromb Haemost 1991;66:49-61. antibodies) should be treated with novel anticoagulant 10. Eby CS. Warfarin-induced skin necrosis. Hematol Oncol therapy (19). Once the signs of irreversible skin injury Clin North Am 1993;7:1291-301. are apparent (hemorrhagic bullae) there is no convincing 11. McGehee WG, Klotz TA, Epstein DJ, Rapaport SI. evidence that the various therapeutic approaches affect Coumarin necrosis associated with hereditary protein C the eventual outcome (21). Nevertheless, if patients are deficiency. Ann Intern Med 1984;101:59-60. carefully monitored in the initial phases of treatment 12. Wattiaux M-J, Herve R, Robert A, Cabane J, Housset B, (localized erythematous-edematous lesions with Imbert JC. Coumarin-induced skin necrosis associated hemorrhagic component) so that excessive doses of with acquired and antiphospholipid warfarin are avoided and vitamin K is administered, it is antibody syndrome. Arthritis Rheum 1984;37:1096-100. possible to prevent progression of skin necrosis (22). 13. Ng T, Tillyer ML. Warfarin-induced skin necrosis Patients should be screened for protein C or S or associated with Factor V Leiden and Protein S deficiency. antithrombin deficiencies, or for the presence of Clin Lab Haematol 2001;23:261-4. antiphospholipid antibodies before beginning warfarin 14. Ward CT, Chavalitanonda N. Atypical warfarin induced therapy (23). Large swings in international normalized skin necrosis. Pharmacotherapy 2006;26:1175-9. ratio should be avoided during initiation of warfarin 15. Abdul-Jabar HB, Geroulakos G, Philpott N, Fareed J, (especially in patients at risk of WISN and in those not Warfarin-induced skin necrosis: a case report, Clin Appl receiving heparin). Finally, early diagnosis (for the Thromb Hemost 2006;12:101-4 occurrence of painful, sudden, well-localized 16. Rose VL, Kwaan HC, Williamson K, Hoppensteadt D, erythematous-edematous lesions with a hemorrhagic Walenga J, Fareed J. Protein C antigen deficiency and component) may lessen the amount of permanent tissue , Am J Clin Pathol 1986;86:653-5. damage (24). 17. Nazarian RM, Laposata M. Anticoagulant therapies. McKean S, Halasyamani L, Bennett AL, eds. Hospital References medicine: just the facts. New York: McGraw-Hill, 2007:506-13. 1. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, 18. Miura Y, Ardenghy M, Ramasastry S, Kovach R, Capra AM, et al. Anticoagulation therapy for stroke Hochberg J. Coumadin necrosis of the skin: Report of prevention in atrial fibrillation: how well do randomized four patients. Ann Plast Surg 1996;37:332-7. trials translate into clinical practice? JAMA 19. Haimovici H, Bergan JJ. Coumadin-induced skin necrosis 2003;290:2685-92. versus venous gangrene of the extremities. J Vasc Surg 2. Gelwix TJ, Beeson MS. Warfarin-induced skin necrosis. 1987;5:655-6. Am J Emerg Med 1998;16:541-3. 20. Eterović D, Titlić M, Culić V, Zadro R, Primorac D. 3. Martin FL. Warfarin-induced necrosis. Am J Nurs Lower contribution of factor V Leiden or G202104 1999;99:53-4. mutations to ischemic stroke in patients with clinical risk 4. Vural M, Usta S, Kaya R. Warfarin-induced benign acral factors: pair-matched case-control study. Clin Appl cutaneous lesions in two cardiac patients with decreased Thromb Hemost 2007;13:188-93.

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